Recent insights into apicomplexan parasite egress provide new views to a kill

Blackman, Michael J.; Carruthers, Vern B.

doi:10.1016/j.mib.2013.04.008

Cited by 54 publications

(55 citation statements)

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“…The exit of T. gondii from mammalian cells is an active process regulated by the parasite itself, and not a breakdown of host cell membranes due to parasite overload (51). We observed loss of TgLCAT delays egress, whereas overexpression of this enzyme hastens this process, suggesting that TgLCAT may act as a facilitator for parasite exit from host cells.…”

Section: Discussionmentioning

confidence: 67%

“…It involves the activity of a parasite-expressed perforin-like protein, TgPLP1 (26,60), and of host enzymes activated by the parasite for rupturing membranes from the inside out (51). The mechanism of action of TgPLP1 may be linked to the protein capability to induce pores (ϳ10 nm in size) in the PV membrane, which may permit passage of effectors across this membrane to aid in egress.…”

Section: Discussionmentioning

confidence: 99%

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A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

Pszenny

Ehrenman

Romano

et al. 2016

Journal of Biological Chemistry

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The protozoan parasite Toxoplasma gondii develops within a parasitophorous vacuole (PV) in mammalian cells, where it scavenges cholesterol. When cholesterol is present in excess in its environment, the parasite expulses this lipid into the PV or esterifies it for storage in lipid bodies. Here, we characterized a unique T. gondii homologue of mammalian lecithin:cholesterol acyltransferase (LCAT), a key enzyme that produces cholesteryl esters via transfer of acyl groups from phospholipids to the 3-OH of free cholesterol, leading to the removal of excess cholesterol from tissues. TgLCAT contains a motif characteristic of serine lipases "AHSLG" and the catalytic triad consisting of serine, aspartate, and histidine (SDH) from LCAT enzymes. TgL-CAT is secreted by the parasite, but unlike other LCAT enzymes it is cleaved into two proteolytic fragments that share the residues of the catalytic triad and need to be reassembled to reconstitute enzymatic activity. TgLCAT uses phosphatidylcholine as substrate to form lysophosphatidylcholine that has the potential to disrupt membranes. The released fatty acid is transferred to cholesterol, but with a lower transesterification activity than mammalian LCAT. TgLCAT is stored in a subpopulation of dense granule secretory organelles, and following secretion, it localizes to the PV and parasite plasma membrane. LCAT-null parasites have impaired growth in vitro, reduced virulence in animals, and exhibit delays in egress from host cells. Parasites overexpressing LCAT show increased virulence and faster egress. These observations demonstrate that TgLCAT influences the outcome of an infection, presumably by facilitating replication and egress depending on the developmental stage of the parasite.The phospholipase A 2 (PLA 2 ) 2 family of serine lipases comprises more than 30 enzymes in mammals. The PLA 2 members hydrolyze the sn-2 ester of phospholipids, yielding lysophospholipid and releasing a fatty acid (1). Approximately one-third of the PLA 2 family members are secreted from cells and display various localizations post-secretion, reflecting their specialized biological functions (2). Among the secretory PLA 2 , lecithin: cholesterol acyltransferase (LCAT; EC 2.3.1.43) is characterized by dual activity, PLA 2 and acyltransferase. In mammals, this enzyme catalyzes the transacylation of the sn-2 fatty acid liberated from various phospholipids (e.g. phosphatidylcholine or phosphatidylethanolamine) to the 3-␤-hydroxyl group on the A-ring of cholesterol, thereby forming cholesteryl esters (3-5). The primary sequence of LCAT is well conserved between mammalian species (6). A structural model for LCAT predicts the conformation of a catalytic triad formed by SerAsp-His residues involved in the phospholipase reaction (7). Mammalian LCATs are primarily expressed in the liver and secreted to the plasma where they circulate in association with HDL (8). These enzymes are components of the reverse cholesterol transport pathway by which cholesterol from peripheral cells is delivered to the liver f...

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

Pszenny

Ehrenman

Romano

et al. 2016

Journal of Biological Chemistry

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“…In P. falciparum merozoites, egress is a tightly regulated process that is initiated 15 hours before exit from the infected erythrocyte 109 . The schizonts activate a series of parasite and host proteases that induce considerable changes in the erythrocyte cytoskeleton, leading to the curling and eversion of the plasma membrane, thus ejecting the parasites into the bloodstream 6,110 (Supplementary information S7 (movie)). It is still unclear whether motility contributes to the rupture of the membranes or whether the osmotic pressure is sufficient to induce merozoite release 111 .…”

Section: Gliding Motility In Vitromentioning

confidence: 99%

“…The zoites rely on a unique mode of substrate-dependent locomotion known as gliding motility; this process is powered by the parasite actomyosin system, which is located underneath its plasma membrane. This gliding machinery, termed the glideosome 2 , enables the zoite to actively propel itself across non-permissive biological barriers (migration), rapidly penetrate various cell types (invasion) [3][4][5] and exit from infected cells (egress) 6 . During host cell entry, the parasites induce the formation of a parasitophorous vacuole, which is derived from the invagination of the host cell plasma membrane.…”

mentioning

confidence: 99%

Gliding motility powers invasion and egress in Apicomplexa

et al. 2017

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| Protozoan parasites have developed elaborate motility systems that facilitate infection and dissemination. For example, amoebae use actin-rich membrane extensions called pseudopodia, whereas Kinetoplastida are propelled by microtubule-containing flagella. By contrast, the motile and invasive stages of the Apicomplexa -a phylum that contains the important human pathogens Plasmodium falciparum (which causes malaria) and Toxoplasma gondii (which causes toxoplasmosis) -have a unique machinery called the glideosome, which is composed of an actomyosin system that underlies the plasma membrane. The glideosome promotes substrate-dependent gliding motility, which powers migration across biological barriers, as well as active host cell entry and egress from infected cells. In this Review, we discuss the discovery of the principles that govern gliding motility, the characterization of the molecular machinery involved, and its impact on parasite invasion and egress from infected cells. NATURE REVIEWS | MICROBIOLOGYADVANCE ONLINE PUBLICATION | 1 REVIEWS © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . ToxoplasmosisA food-borne infection caused by the parasite Toxoplasma gondii. The infection is usually mild or even asymptomatic, but can have serious consequences in patients who are immunocompromised and for the fetus in the case of primary infection during pregnancy. SporozoitesThe infectious and motile stage produced in oocysts and transmitted by the definitive host. TachyzoitesThe motile and fast-replicative stage of Toxoplasma gondii that is able to invade any nucleated cell in the host. MerozoitesThe stage of Plasmodium spp. that infects erythrocytes, in which it initiates a new asexual life cycle. Actomyosin systemA complex that comprises actin filaments, myosin and associated proteins, and that is involved in movement. GlideosomeA molecular complex that powers gliding motility in apicomplexan parasites.motility, invasion and egress. In this Review, we focus primarily on the T. gondii tachyzoite, for which functional studies were first carried out, and we compare and contrast this with the motile stages of malaria parasites -the sporozoite, merozoite and ookinete.Emergence of the capping model The motility of Apicomplexa (historically named Sporozoa) has caught the attention of scientists for more than a century 8 and was named gliding motility early on, on the basis of microscopic observations Nature Reviews | Microbiology www.nature.com/nrmicro © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . of live specimens (FIG. 2; Supplementary information S1-S5 (movies)). This mode of motility differs substantially to amoeboid motion involving pseudopods, and from the ciliary and flagellar motion used by most unicellular organisms. The main hypothesis to explain gliding motility in the early days was slime secretion, as seen in slugs; ...

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“…The MACPF family is extremely diverse − its members function in immunity and pathogenesis across all kingdoms of life (Kondos et al, 2010). For example, MACPF proteins facilitate the invasion and/or proliferation of intracellular pathogens, such as Toxoplasma gondii, Plasmodium falciparum and Chlamydia, all of which must traverse cellular membrane barriers during their life cycles (Blackman and Carruthers, 2013;Taylor andNelson, 2014, Wade and. In addition, several MACPF proteins have roles in embryonic development (Estévez-Calvar et al, 2011;Johnson et al, 2015) and in neural migration (Kawano et al, 2004;Giousoh et al, 2015).…”

Section: The Macpf-cdc Superfamilymentioning

confidence: 99%

The membrane attack complex, perforin and cholesterol-dependent cytolysin superfamily of pore-forming proteins

Lukoyanova

Hoogenboom

Saibil

2016

Journal of Cell Science

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The membrane attack complex and perforin proteins (MACPFs) and bacterial cholesterol-dependent cytolysins (CDCs) are two branches of a large and diverse superfamily of pore-forming proteins that function in immunity and pathogenesis. During pore formation, soluble monomers assemble into large transmembrane pores through conformational transitions that involve extrusion and refolding of two α-helical regions into transmembrane β-hairpins. These transitions entail a dramatic refolding of the protein structure, and the resulting assemblies create large holes in cellular membranes, but they do not use any external source of energy. Structures of the membrane-bound assemblies are required to mechanistically understand and modulate these processes. In this Commentary, we discuss recent advances in the understanding of assembly mechanisms and molecular details of the conformational changes that occur during MACPF and CDC pore formation.

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Recent insights into apicomplexan parasite egress provide new views to a kill

Cited by 54 publications

References 46 publications

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

A Lipolytic Lecithin:Cholesterol Acyltransferase Secreted by Toxoplasma Facilitates Parasite Replication and Egress

Gliding motility powers invasion and egress in Apicomplexa

The membrane attack complex, perforin and cholesterol-dependent cytolysin superfamily of pore-forming proteins

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